HR001120S0019-15.pdf

Small Business Innovation Research (SBIR) Opportunity Announcement

HR001120S0019-15

Replicating Human Tissue Complexity for High Throughput Testing

Which program will fund this topic?

SBIR

What type of proposals will be accepted?

Phase I Only

Technology Area(s): Biomedical, Chemical/Biological Defense DARPA Program: Friend or Foe

I. INTRODUCTION

The Defense Advanced Research Projects Agency (DARPA) Small Business Programs Office (SBPO) is issuing an SBIR/STTR Opportunity (SBO) inviting submissions of innovative research concepts in the technical domain(s) of Biomedical, Chemical/Biological Defense. In particular, DARPA is interested in understanding the feasibility of Replicating Human Tissue Complexity for High Throughput Testing.

This SBO is issued under the Broad Agency Announcement (BAA) for SBIR/STTR, HR001120S0019. All proposals in response to the technical area(s) described herein will be submitted in accordance with the instructions provided under HR001120S0019, found here:

https://beta.sam.gov/opp/b8abeb02f16a4450b2c2f859fc00c177/view.

a. Eligibility The eligibility requirements for the SBIR/STTR programs are unique and do not correspond to those of other small business programs. Please refer to Section 3.1, Eligible Applicants, of HR001120S0019 for full eligibility requirements.

b. Anticipated Structure/Award Information Please refer to Section 1, Funding Opportunity Description, provided in HR001120S0019 for detailed information regarding SBIR/STTR phase structure and flexibility.

For this SBO, DARPA will accept Phase I proposals for the cost of up to $225,000 for a 6- month period of performance.

Proposers should refer to Section 4, Application and Submission Information, of HR001120S0019 for detailed proposal preparation instructions. Proposals that do not comply with the requirements detailed in HR001120S0019 and the research objectives of this SBO are considered non-conforming and therefore are not evaluated nor considered for award.

Phase I proposals shall not exceed 20 pages. Phase I commercialization strategy shall not exceed 5 pages. This should be the last section of the Technical Volume and will not https://beta.sam.gov/opp/b8abeb02f16a4450b2c2f859fc00c177/view count against the 20-page limit. Please refer to Appendix A of HR001120S0019 for detailed instructions on Phase I proposal preparation.

Should DARPA have funding available and decide to proceed with a Phase II, proposers awarded a Phase I contract will be eligible to submit a proposal for Phase II and will be contacted by the DARPA Small Business Programs Office at the appropriate time during their Phase I period of performance. If selected, Phase II will have a period of performance of up to 24 months at $1 million, with a 12-month option of $500,000.

c. Human Subjects Research (HSR)/Animal Use Proposers that anticipate involving HSR or animal use must comply with the approval procedures detailed at http://www.darpa.mil/work-with-us/additional-baa. For more information, refer to Section 4.7, Human Subjects/Research/Animal Use, of

HR001120S0019.

Proposers are highly encouraged to clearly segregate research tasks from human and/or animal testing tasks to allow for partial funding while internal and Department of Defense (DoD) approvals are being obtained.

d. Evaluation of Proposals Section 5, Evaluation of Proposals, in HR001120S0019 provides detailed information on proposal evaluation and the selection process for this SBO.

e. Due Date/Time Full proposal packages (Proposal Cover Sheet, Technical Volume, and Price/Cost Volume inclusive of supporting documentation) must be submitted via the DoD SBIR/STTR Proposal Submission website per the instructions outlined in HR001120S0019 no later than 12:00 pm ET, September 22, 2020.

II. TOPIC OVERVIEW

a. Objective

This SBIR would enhance detection of pathogens from complex samples by developing a high-throughput, low-cost, physiologically realistic model system that demonstrates human tissue hierarchy and cellular heterogeneity and, critically, is compatible with high-speed microfluidics.

b. Description Warfighters are travelers, continually exposed to new environments and new pathogens.

These new pathogens are increasingly likely to emerge and spread due to changes in the environment, rising global population, and the ready availability of global travel. This necessitates new and improved high-throughput tools that can identify new threats, reveal how they are pathogenic, and screen potential treatments.

Current model systems that can examine the interactions between host and pathogen are limited either by the time required to return an answer or by the level of complexity inherent in the system. For instance, while tissue culture cells have a relatively low cost http://www.darpa.mil/work-with-us/additional-baa and a high speed turn-around, they do not replicate host complexity. Animal models clearly demonstrate physiologically relevant responses to a pathogen, but also require significant time, money, and often extensive adaptation or modification to recapitulate human disease, further increasing costs and delay. Recent efforts using organized and differentiated human cells to represent a human, such as organoids and organ-on-a-chip technologies, show promise in bridging these gaps. Yet, to be useful in detecting novel pathogens, they still require much greater throughput and significantly lower costs.

DARPA seeks technologies that eliminate the bottleneck in determining the pathogenicity of unknown bacteria by achieving the complexity of an in vivo model while matching the speed and throughput of microfluidics-based assays.

To ensure relevance to pathogen detection, the technology should:

Be based on human cells and tissues Preserve cellular diversity and hierarchy Demonstrate differential responses to pathogens similar to in vivo models, producing more information than tissue culture cells

Of particular interest would be a system that captures the genetic diversity of a population, in contrast to the constrained diversity of immortalized cell lines.

Additionally, technology developed through this SBIR should be high-throughput, capable of testing at least 1,000 pathogen/host interactions in a day, have the capability to replicate tissue-level responses, and be miniaturized for high-throughput platform assays.

The technology should be available “on demand” by reconstitution from frozen stocks of cells. Lastly, technology should be transferrable to new users and adaptable to the high throughput technologies associated with pathogen and drug screening

c. Phase I Phase I should develop technology that replicates the host’s response to at least two pathogenic and two non-pathogenic organisms. System complexity should exceed that of tissue culture and represent pathogenicity comparable to in vivo models. Lastly, proposers must identify concepts and methods to scale-up for high-throughput testing, and provide a plan for practical deployment of the proposed technology.

Schedule/Milestones/Deliverables Month 1: Report comparing the developing technology to both a relevant tissue culture cell model and actual or reported human and in vivo model phenotypes using ≥3 tissue relevant bacterial pathogenic species.

Month 3: Report of studies to identify and define differential markers of host susceptibility consistent with establishing performance goals.

Month 4: Demonstrate and report a prototype assay that can differentiate pathogenic from non-pathogenic bacteria with quantification of the error rate, signal, and noise.

Month 5: Interim report comparing response to pathogen between cells before and after freeze-thaw.

Month 6: Final Phase I report summarizing approach; comparison of how technology’s response replicates host complexity significantly as compared to tissue culture cells; comparison with other state-of-the-art methodology;

quantification of accuracy; quantification of robustness to errors, noise and model or assessment of the limits required to meet performance goals.

d. Phase II Phase II will focus on advancing the technology’s performance—increasing the breadth of host/pathogen markers, demonstrating rapid technology deployment upon receipt, and scaling the technology for commercialization. The result of this SBIR will be a prototype that could be readily tested for high-throughput analysis and for ease of operation by a separate lab. Proposers should demonstrate commercial merit and feasibility of the technology to be disseminated to downstream users.

The ultimate system must demonstrate the capability to identify host responses to pathogens with a testing throughput of at least 1,000 pathogens/day. Additionally, the technology must demonstrate the capacity to be rapidly brought online from either frozen or other preservation methods to processing at least 5,000 pathogens in a week.

Phase II option year would involve work with academic or commercial partners to demonstrate the technology.

Schedule/Milestones/Deliverables Month 2: New Capabilities Report, that identifies additions and modifications that will be researched, developed, and customized for incorporation in the pilot demonstration.

Month 4: Interim decision report on marker technology describing relative strengths and weaknesses of selected reporters, and results of tests demonstrating their capacity to meet the throughput goals.

Month 12: Demonstrate and deliver a report for a prototype system that can identify at least 3 host/pathogen responses relevant to niche finding, immune system evasion, or the degradation of membranes and that is compatible with high-throughput sample processing and decision making for at least 3 pathogens relevant to the target tissue.

Month 15: Report describing the examination of additional tissue types for technology expansion including examination of cellular diversity and hierarchy and comparison of the ability to differentiate pathogen vs. non pathogen.

Month 18: Report on demonstration of the technology with models of at least 3 more relevant tissue types derived from at least 3 more genetically distinct tissues.

Month 24: Demonstrate and deliver a report for a prototype system that can identify at least 10 responses of the host cells to a pathogen. The approach should be compatible with high-throughput sample processing, should demonstrate a range of responses, and should stem from interactions with at least 3 pathogens relevant to the target tissue.

Phase II Option Phase II option year would focus on improving performance by working with academic or commercial partners to increase the number of tissues that can be deployed, and the speed with which they can by employed. The technology should also be refined and scaled for commercialization.

Month 30: Report on successful demonstration of the technology by a team without prior experience with the technology. A successful demonstration would identify a biological interaction revealed by the multicellular construct that is not seen in individual cells or in cultures of immortalized cells.

Month 36: Report on successful demonstration of the technology by a team without prior experience with the technology. A successful demonstration would identify at least 3 different biological interactions revealed by the multicellular construct that is not seen in individual cells or in cultures of immortalized cells.

The test must be performed on the prototype device using components delivered and stored in a manner consistent with future commercialization, such as being thawed from stock that had been frozen and shipped.

e. Dual Use Applications (Phase III) Potential customers include government agencies with interests in high-throughput pathogen detection as well as other government and non-government partners working in areas from basic research to clinical applications. Technology developed may be transitioned directly as tools or advanced therapies, or licensed as intellectual property to speed development of advanced therapies by others.

f. References [1] Simian, M., and Bissell, M. Organoids: A historical perspective of thinking in three dimensions. Journal of Cell Biology. (2017) 216(1): 31-40. DOI:10.1083/jcb.201610056

[2] Fatehullah, A., Tan, H.S., and Barker, N. Organoids as an in vitro model of human development and disease. Nature Cell Biology. (2016) 18(3): 246-254.

DOI:10.1038/ncb3312

g. Keywords High-throughput; Pathogen-detection; Tissue complexity; Cellular hierarchy; Alternative in vivo models

III. SUBMISSION OF QUESTIONS

DARPA intends to use electronic mail for all correspondence regarding this SBO. Questions related to the technical aspect of the research objectives and awards specifically related to this SBO should be emailed to HR001120S0019@darpa.mil. Please reference BAA HR001120S0019-15 in the subject line. All questions must be in English and must include the name, email address, and telephone number of a point of contact.

DARPA will attempt to answer questions in a timely manner; however, questions submitted within seven (7) calendar days of the proposal due date listed herein may not be answered.

DARPA will post a consolidated Frequently Asked Questions (FAQ) document. To access the posting, please visit: http://www.darpa.mil/work-with-us/opportunities. Under the mailto:HR001120S0019@darpa.mil http://www.darpa.mil/work-with-us/opportunities

HR001120S0019-15 summary, there will be a link to the FAQ. The FAQ will be updated on an ongoing basis until one week prior to the proposal due date.

In addition to the FAQ specific to this SBO, proposers should also review the SBIR/STTR General FAQ list at http://www.darpa.mil/work-with-us/opportunities?tFilter=&oFilter=29934. Under the HR001120S0019 summary, there is a link to the general FAQ.

Technical support for the Defense SBIR/STTR Innovation Portal (DSIP) is available Monday through Friday, 9:00 a.m. – 5:00 p.m. ET. Requests for technical support must be emailed to DoDSBIRSupport@reisystems.com with a copy to HR001120S0019@darpa.mil.

http://www.darpa.mil/work-with-us/opportunities?tFilter=&oFilter=29934 http://www.darpa.mil/work-with-us/opportunities?tFilter=&oFilter=29934 mailto:DoDSBIRSupport@reisystems.com mailto:HR001120S0019@darpa.mil